Objective

PACE aims to transform the treatment of patients suffering from critical limb ischemia (CLI), a disease with high medical need, because of limited treatment options and poor outcome by applying a novel, off-the-shelf allogeneic placenta-derived stromal cell product (PLX-PAD). Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death (1-year amputation-free survival <60%; 10-year mortality 70%). CLI has a strong social impact and its incidence is rising worldwide, including in Europe. The prevalence of CLI in the population aged 60–90 years is estimated as 1% (0.5–1.2%) with male to female ratio around 3:1. We will evaluate the efficacy, tolerability and safety of multiple intramuscular injections of HLA-unmatched allogeneic PLX-PAD for the treatment of CLI patients who are unsuitable for revascularization, in a randomized, double-blind, multicentre, placebo-controlled, parallel group phase II study. The European Medicine Agency (EMA) accepted PLX-PAD as pilot project for the new “Adaptive Pathways to Patients” to force timely access for patients to the new therapeutic option. The PACE consortium will go beyond the traditional clinical trial endpoints of safety and efficacy, by state-of-the-art characterizing molecular and functional signature of the PLX-PAD product(s), in depth investigating mechanisms-of-action of PLX-PAD therapy, and exploring biomarkers for understanding response/non-response in particular patients (stratification and therapy response markers). PACE partners are world-leading experts in scalable, clinical grade 3D-cell manufacturing approved by authorities, preclinical and clinical cell therapy, and biomarker analyses with well recognized expertise in designing and performing clinical trials, including those with Advanced Therapy Medicinal Products (ATMPs) integrated with in-patient biomarker and mechanistic side-studies.

"Critical limb ischemia (CLI) is at the severe end of peripheral artery disease (PAD) spectrum when limb perfusion is reduced to tissue loss. Nutrient blood flow to the tissues and microcirculation exchange are seriously affected. As such CLI is associated with irreversible disability due to limb amputation, increased mortality rates and overall poor quality of life. Therapies targeting only the re-establishment of vascular patency (revascularization) and/or nascent collateral vessel formation by supporting vascularization have proven ineffective in a significant proportion of patients indicating the ischemic muscle tissue is not dispensable and therefore a “restoration of flow approach” is not independently sufficient to rescue the limb. It is likely that myopathy and vasculopathy are interrelated components of a coordinated tissue response to CLI. Thus, current clinical interventions are largely ineffective and therapeutic angiogenesis-based trials have shown limited if any efficacy, highlighting the dire need for new ideas and novel therapeutic approaches.Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death (1-year amputation-free survival <60%; 10-year mortality 70%). CLI has a strong social impact and its incidence is rising worldwide, including in Europe. The prevalence of CLI in the population aged 60–90 years is estimated as 0.5–1.2% with male to female ratio around 3:1. The major risk factors for PAD include smoking, hyperlipidemia, hypertension, and, particularly for development of CLI, diabetes. Diabetic patients are, at least, fivefold more likely to develop CLI than non-diabetic patients. The application of gene- and cell-based ATMP therapies to promote angiogenesis has been proposed as a novel concept to treat lower-limb CLI, particularly for patients with no options for revascularization, Proof of concept was demonstrated in animal models leading to clinical trials. The safety of these biologic therapies has been demonstrated, with no evidence of ""off-target"" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Despite some failures the results obtained from the recent literature data have confirmed the putative beneficial role of cell therapy in improving overall ischemic symptoms in patients with CLI and their quality of life. However, there are several open questions regarding the optimal cell types, dosing, route of administration, combination, patient phenotype, and critically, proof of efficacy in large controlled trials. Most importantly, recent clinical studies have several limitations. Therefore, there is a need for i) well characterized off-the-shelf cell products manufactured in well-controlled, scalable, and robust GMP-procedures; and ii) more detailed analyses of patients prior to cell treatment to define stratification parameters, iii) better understand pharmacodynamics and iv) describe mode-of-action to identify (non)response to treatment or adverse effects as early as possible via state of the art biomarkers.What are the overall objectives? To evaluate the efficacy, tolerability and safety of local intramuscular injections of HLA-unmatched allogeneic PLX-PAD cell products for the treatment of patients with CLI with minor tissue loss who are unsuitable for revascularization or had undergone several procedures in the past and are unlikely to benefit from additional interventions. To present a model for the clinical development of a cell product using the new “Adaptive Pathways to Patients” (defined by the EMA). To further characterize the molecular and functional signature of the PLX-PAD cell product(s). To look beyond the traditional clinical trial endpoints of safety and efficacy, actively investigating the mechanisms of action of PLX-PAD therapy, exploring biomarkers in order to understand (non-)response in particular patien"

PACE aims for advancing clinical application of the “off-the-shelf” allogeneic placenta-derived stromal cell product (PLX-PAD) for critical limb ischemia (CLI) – a clinical indication with high unmet medical need – by performing a clinical trial integrated with mechanism-based research. Within the reporting period, we prepared and started a randomized, double-blind, multicenter, placebo-controlled, parallel group phase III trial for the treatment of CLI patients who are unsuitable for revascularization. Clinical grade PLX PAD cell product batches were successful manufactured and used/stored for patients’ treatment. In addition samples of these cell product batches were send for accompanying in depth characterization to the partners, including HLA-typing. At the end robust manufacturing process of PLX-PAD cell products is shown and ready for patient applications within the trial. In addition, follow-up examinations of study patients started and increases our understanding on the mode-of-action of PLX-PAD. In addition to the scientific progress, the overall awareness of the disease CLI and the PACE project increased due to several dissemination activities performed by all partners. This includes for example a project website, press releases, project-specific, flyers, and information material for the clinical sites as well as for the study subjects. Altogether PACE can be a model for advancing the clinical development of ATMPs by an integrative approach based on a well-defined cell product, state-of-the-art clinical trial and accompanying biomarker and mechanistic in-patients studies.

The PACE consortium is investigating the efficacy of a regenerative treatment for patients with CLI and minor tissue loss, who are unsuitable for revascularization. The treatment is an off-the-shelf allogeneic placenta-derived stromal cell product. PACE is a valuable example of Public-Private investment that would improve the quality of life of patients between 60–90 years old a group estimated as 1% of the European population, with a male to female ratio around 3:1. CLI has a strong social impact and its incidence is rising worldwide, including in Europe.A successful outcome for the PACE clinical trial can be rapidly translated into a new therapy for patients suffering from critical limb ischemia (CLI), a disease with high medical need and limited treatment. At the end, PACE will have significant impact on health services, research and patient management, and will generate guidelines for the development of other cell-based therapies according to the regulatory categorization into the “fast track” “Adaptive Pathways to Patient” program.